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On April 21, 1930, a major fire killed 322 inmates and seriously injured 150.[2] The fire was the deadliest prison fire in United States history.[3] The fire broke out on scaffolding erected for the construction of an extension. Reports say that many guards refused to unlock cells when smoke entered the cell block and left the prisoners in their cells, although some did provide help. Some inmates overpowered a guard and took his keys, which they used to rescue other prisoners. However, a riot developed and firefighters arriving to fight the blaze were attacked with rocks.[4]

A cordon of penitentiary guards was deployed about the towering prison walls. Other squads took up vantage points in guard towers and by this time 500 soldiers from Fort Hayes, a local military post, were on the scene. Machine guns were placed at the gates and on the walls. Bayonets were fixed and the troopers were ordered to shoot to kill. A troop of National Guardsmen soon augmented the regulars, and 30 minutes after the fire started the prison was completely surrounded.[5]

The incident was the subject of then-inmate Chester Himes' story To What Red Hell, published in Esquire in 1934, as well as to his 1952 novel, Cast the First Stone, republished unabridged in 1998 as Yesterday Will Make You Cry.

In 1885, the penitentiary became the site for executions, which had been carried out by local law enforcement officials up to that time. At first, prisoners condemned to death were executed by hanging, but in 1897 the electric chair replaced the prison's gallows. A total of 315 prisoners, both men and women, were electrocuted between 1897 and 1963, when the death penalty was halted in Ohio.[6] A number of women served on death row in the prison and ultimately faced execution either by hanging or in the electric chair.

The prison was the site of the "Halloween Riot", on October 31, 1952, which left one inmate dead and four injured,[7] as well as the riot of August 1968, which ended with five dead inmates, five injured inmates and seven injured officers.[8]